1. Field of the Invention
The present invention relates to compounds for treating ischemic diseases, more particularly to aporphine and oxoaporphine compounds that can be used to prevent or treat ischemic diseases based on a mechanism of maintaining or increasing the endothelial nitric oxide synthase (eNOS).
2. Background of the Invention
With the progress of society and the advance in sciences and technology, life expectancy gradually increases. Many people now suffer from various diseases due to old age, diet, obesity, lack of exercise or living under stress. Among these diseases, ischemic diseases are among the main causes of death and physical impairment. Ischemic diseases have a major impact and cause substantial loss to people, family, society and the state. Therefore, it is important to find agents to prevent the ischemic diseases.
Among various ischemic diseases, ischemic stroke has a high rate of morbidity, mortality, handicap and recurrence, and it is a common disease among middle-aged and old people. Occlusion of the extracranial or intracranial arteries, which supply blood to the brain, may cause brain ischemia and hypoxemia, resulting in a series of acute clinical symptoms (i.e. ischemic stroke). If blood supply cannot be restored in time, nerve cells, glial cells, vascular endothelial cell and smooth muscle cells will die, leading to cerebral infarction and cerebral thrombosis.
For the ischemic stroke, the thrombolytic agent, tissue plasminogen activator, is the only medicament that can re-open occluded blood vessels. Tissue plasminogen activator is also the only medicament that has been approved for treating thromboembolic stroke by the Food and Drug Administration in the U.S., and it was also approved by the Health Administration in Taiwan in 2001. However, because patients may suffer cerebral hemorrhagic complication after using a thrombolytic agent, this agent is strictly restricted in its use in a therapeutic window, i.e. “critical period.” This drug should be injected intravenously within 3 hours after stroke, or injected intra-arterially with the aid of cerebral angiography to directly lyse the thrombus within 6 hours after stroke.
Other conventional blood vessel unblocking agents, such as anticoagulants and platelet aggregation inhibitors, can only prevent continued thrombus formation, but cannot lyse the thrombus to re-open occluded blood vessels. In addition, brain tissue protecting agents (such as Piracetam) also offer a promising therapy for thrombosis. However, these agents also need to be administrated within 6 hours after stroke to achieve a significant effect.
Recent studies show that blood clot dissolving agents can trigger the production and release of oxygen free radicals, platelet activating factor (PAF), and excitotoxic neurotransmitter, such as glutamate, which may act as N-methyl-D-aspartic acid (NMDA) to stimulate the NMDA receptor and consequently lead to neuronal cell death. Though MK801, an NMDA receptor antagonist, can reduce the injury (or infarction) in ischemia or ischemia-reperfusion brain tissue, the hypothermic effect, suppression of memory and other side effects of this agent prevent it from being used as a therapeutic agent.